Thiazole-5-Methanol

Product Name Thiazole-5-Methanol
Alias 5-(Hydroxymethyl)thiazole
Einecs 249-790-4
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, Thiazole-5-Methanol is supplied with ≥97% purity (GC) and ≤0.5% water content (K.F.), making it suitable for moisture-sensitive heterocyclic building block synthesis.

Specifications

HS Code	588421
Chemical Formula	C4H5NOS
Molar Mass	115.15 g/mol
Appearance	Solid
Melting Point	N/A
Boiling Point	N/A
Solubility In Water	Slightly soluble
Solubility In Organic Solvents	Soluble in common organic solvents
Density	N/A
Odor	Characteristic odor
Ph	N/A
Stability	Stable under normal conditions
Hazard Class	Irritant

As an accredited Thiazole-5-Methanol factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of Thiazole - 5 - Methanol packaged in a sealed, chemical - resistant container.
Shipping	Thiazole - 5 - Methanol is shipped in sealed, corrosion - resistant containers. Adequate cushioning is used to prevent breakage. It follows strict chemical transportation regulations to ensure safe transit due to its chemical nature.
Storage	Thiazole - 5 - Methanol should be stored in a cool, dry, well - ventilated area, away from heat sources and ignition points. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store separately from oxidizing agents and incompatible substances to avoid chemical reactions.

Application of Thiazole-5-Methanol

Production of enantiomerically pure active pharmaceutical ingredients (APIs) containing a thiazole moiety hinges on the availability of a regiospecific 5-hydroxymethyl handle that resists premature oxidation during multi-step syntheses. In a representative route toward an azole-class antifungal candidate, Thiazole-5-Methanol is converted into a chiral ether intermediate destined for late-stage coupling with a triazole-epoxide scaffold. The downstream manufacturing process is conducted in a 5000 L glass-lined reactor under nitrogen blanketing, where Thiazole-5-Methanol (1.0 molar equivalent) is combined with a tosyl-protected chloromethyl-aryl precursor at a ratio of 1.0:1.15 in anhydrous acetonitrile. Caesium carbonate (1.5 eq) powder is charged at 0–5 °C over 90 minutes to suppress exotherms that risk racemization of the adjacent stereocenter. The slurry is held at 60–65 °C for 12 hours, with in-process control by chiral HPLC (Chiralpak AD-H column, 95:5 hexane:isopropanol, 1.0 mL/min) to confirm diastereomeric excess ≥ 99.0%. Upon completion, the mixture is filtered through a 0.5 μm cartridge and concentrated in a wiped-film evaporator at 40 °C jacket temperature and 15 mbar absolute pressure. The residue is recrystallized from n-hexane/ethyl acetate (4:1 v/v) to deliver an intermediate with HPLC purity exceeding 99.5 area% and a residual acetonitrile level below 410 ppm, meeting USP ⟨467⟩ Class 2 requirements. The entire campaign operates under ICH Q7 guidelines, specifically clause 10 (materials management) and clause 19 (process controls), with solvent recovery loops validated according to ICH Q3C. The terminal finished product manufactured from this intermediate is the crystalline freebase of a third-generation triazole antifungal API, formulated into a lyophilized powder for intravenous administration against invasive aspergillosis.

When the 5-Chloromethyl Intermediate Demands a More Selective Precursor

Synthesis regimens for novel nematicidal organophosphates and neonicotinoid analogues frequently cross-react when the electrophilic component is a dihalogenated heteroaromatic. Thiazole-5-Methanol circumvents the positional ambiguity inherent in 5-chloromethyl thiazole derivatives by providing a hydroxyl nucleophile that can be selectively activated without competing N-alkylation. In a validated production sequence for a pymetrozine-class building block, the alcohol is reacted with 2-chloro-5-chloromethylpyridine in dimethyl sulfoxide (8 volumes) containing powdered 99% KOH (1.3 eq). The addition rate of Thiazole-5-Methanol is controlled at 1.05 molar equivalents relative to the chloropyridine, avoiding excess that would necessitate chromatographic removal downstream. Batch temperature is maintained at 25–30 °C through jacket cooling, and the absence of water ensures the alkoxide generates in situ. After 4 hours the slurry is quenched into chilled water and processed through a counter-current centrifugal extractor (CINC V-2 type) operating at 3000 rpm, using methyl tert-butyl ether as the organic stream. The organic phase is concentrated under 20 mbar and finished in a short-path distillation unit at 128 °C, 0.8 mbar, yielding the pyridyl-thiazole ether as a light yellow oil with GC purity > 98.5%. The manufacturing site holds ISO 17025 accreditation for the QC laboratory; the intermediate is registered under EU REACH at a tonnage band of 10–100 tonnes per annum and complies with the relevant residue criteria embedded in FAO/WHO specifications for corresponding plant protection product evaluation. End-use formulations derived from this intermediate include a 50% wettable powder (WP) and a flowable suspension concentrate (SC) for soil-applied nematode control.

How Does a Thiazole Methanol Precursor Shape The Savory Notes of Process Flavors?

Thermal generation of meat-like aroma in low-fat extruded snacks often fails to replicate the sulfury depth contributed by animal-derived thiamin-rich extracts. Thiazole-5-Methanol serves as a precursor in model Maillard reaction systems, where its ring-opened fragments re-cyclize in the presence of cysteine degradation products to yield 2-methyl-4,5-dihydrothiazole and related roasted, beefy volatiles. In a commercial hydrolyzed vegetable protein (HVP)-based process flavor manufacture, the compound is dosed at 0.3–0.5 wt% of the total reaction mass, alongside L-cysteine hydrochloride monohydrate (1.2 wt%), D-xylose (0.8 wt%), and thiamine hydrochloride (0.15 wt%) dissolved in HVP paste (45% solids). The mixture is heated in a 2000 L jacketed vessel fitted with a slow-agitator anchor and a reflux condenser; the temperature ramp reaches 110 °C over 25 minutes and is held for 90 minutes at pH 5.0–5.5 adjusted with food-grade sodium hydroxide. After rapid cooling to 25 °C, the reaction mass is homogenized with maltodextrin (DE 12–15) as a carrier at a 1:1 dry weight ratio and spray-dried in a Niro-type tower with inlet air at 180 °C and outlet at 90 °C, yielding a free-flowing powder with moisture < 5%. This process flavor complies with European Regulation 1334/2008/EC on food flavourings and undergoes an IFRA Standards usage-level evaluation to ensure total heterocyclic amine concentrations do not exceed the applied restrictions for category 7 (savory snacks). The terminal consumer product is a roasted beef-type powdered seasoning sold in bulk to instant noodle manufacturers and plant-based meat analogue producers.

Corrosion Inhibition Isotherm and Pickling Bath Longevity

Steel pickling in hydrochloric acid at elevated temperatures accelerates substrate dissolution unless a heterocyclic inhibitor modifies the electrochemical double layer. Thiazole-5-Methanol adsorbs onto low-carbon steel surfaces via coordination of the nitrogen and sulfur lone pairs with vacant d-orbitals of iron, and the pendant hydroxymethyl group facilitates binding to the oxidized surface film, shifting the corrosion potential anodically in potentiometric scans. Batch-wise immersion tests conducted per ASTM G31-72 in 10% (w/w) HCl at 55 ± 1 °C over 6 hours indicate that a standalone concentration of 0.8 wt% achieves an inhibition efficiency plateau; further increases to 1.2 wt% yield negligible improvement. When combined with 0.05 wt% potassium iodide, a pronounced synergy emerges: the required Thiazole-5-Methanol dosage drops to 0.2 wt% to maintain the same efficiency, presumably due to iodide ion pre-adsorption facilitating the protonated thiazole species’ approach. The material is delivered to the pickling line as a 25% (v/v) concentrate blended in ethylene glycol monobutyl ether, metered into the acid circulation tank through a magnetically coupled gear pump at a rate proportional to fresh acid replenishment. The bath is operated at 55–65 °C with continuous filtration through 5 μm polypropylene cartridges, and ferrous ion concentration is monitored online via ORP analyzer; the bath is typically discarded when Fe²⁺ exceeds 150 g/L. Electrochemical verification of inhibitor persistence follows ASTM G5-14 and the polarization resistance method defined in ISO 17475:2005. The final industrial product is a reconditioned acid solution used directly in continuous coil pickling of low-carbon hot-rolled strip, extending acid service life by 30–40% relative to uninhibited baths.

Table 1. Standardized Test Parameters for Evaluating Thiazole-5-Methanol Inhibition in Hydrochloric Acid
Condition	Specification	Reference Method
Coupon material	SAE 1010 cold-rolled steel, 600-grit finish	ASTM G1-03
Acid concentration	10 ± 0.5% HCl	—
Immersion period	6 h	ASTM G31-72
Temperature control	55 ± 1 °C	ASTM G31-72
Solution volume-to-area ratio	40 mL/cm²	ASTM G31-72
Potentiodynamic scan rate	0.166 mV/s	ASTM G5-14
Reference electrode	Saturated calomel (SCE)	ISO 17475:2005

Continuous electrodeposition of fully bright nickel from Watts-type solutions demands an auxiliary brightener that shifts the reduction overpotential without introducing sulfur embrittlement beyond the level tolerated by subsequent chromium plating. Thiazole-5-Methanol, classified as a Class I carrier enhancer, functions by preferential adsorption on high-current-density sites, refining grain structure and promoting the co-deposition of a primary brightener such as saccharin or a benzene sulfonamide derivative. The compound is integrated into the additive package via a premix step: 8 kg of Thiazole-5-Methanol is dissolved in 200 L deionized water at 50 °C with 12 kg of a proprietary alkyne-based brightener and 6 kg sodium allyl sulfonate, then diluted to a final concentrate volume of 1000 L with a stock solution containing 450 g/L nickel sulfate hexahydrate and 50 g/L boric acid. In the operating bath — maintained at 55 ± 2 °C and pH 4.0–4.3 — the steady-state concentration of Thiazole-5-Methanol is held between 0.08 and 0.12 g/L, verified by HPLC-UV analysis of a filtered sample at λ = 254 nm against an external standard. The optimal current density window of 2–6 A/dm² is established through Hull cell tests on brass panels at 2 A cell current for 5 minutes, with the resulting panel showing a bright, ductile range of 5.5 cm under visual and profilometry inspection. The automatic plating line replenishes the additive via an ampere-hour counter coupled to a diaphragm dosing pump, while continuous filtration through 1 μm polypropylene bags removes particulate. Plated articles must conform to the thickness and ductility requirements of ASTM B456-17 and the neutral salt spray resistance of ISO 4527:2003; bath operation is guided by the analytical control schedules of DIN 50970. The finished good is a decorative nickel underlayer plated onto zinc die-cast bathroom fittings and ABS automotive grille parts, later top-coated with a microporous chromium layer to achieve a CASS test rating of 9.5/10.

Table 2. Multi-Jurisdictional Regulatory Reference for Thiazole-5-Methanol Downstream Applications
Application Segment	Key Standard / Framework	Jurisdiction / Authority
Pharmaceutical intermediate	ICH Q7 (GMP for APIs), USP ⟨467⟩ Residual Solvents	FDA (USA), EMA (EU), PMDA (Japan)
Agrochemical intermediate	FAO/WHO specifications, EU 1107/2009, REACH	EFSA (EU), EPA-FIFRA (USA)
Process flavouring	Regulation 1334/2008/EC, IFRA Standards	EFSA, FEMA Expert Panel (USA)
Corrosion inhibitor	ASTM G31-72, ISO 17475:2005	Global industrial practice (NACE)
Electroplating additive	ASTM B456-17, ISO 4527:2003, DIN 50970	Global (ANSI, ISO), OEM specifications

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Certification & Compliance

Thiazole-5-Methanol is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

Regulatory Control of Mutagenic Impurities in Cefditoren Pivoxil Synthesis

In the manufacture of the oral cephalosporin antibiotic cefditoren pivoxil, thiazole-5-methanol serves as the cornerstone for constructing the C-3 vinyl-thiazole side chain via a Horner-Wadsworth-Emmons olefination. The product is first converted to the corresponding phosphonate ester; residual starting alcohol and de-halogenated byproducts originating from prior bromination steps must be controlled below 0.10% (area percent by HPLC) to satisfy ICH M7 thresholds for non-mutagenic process impurities in APIs. Process analytical technology (PAT) integration, employing a Mettler Toledo ReactIR 45m with a diamond ATR probe and a K6 conduit, enables real-time tracking of the carbonyl intermediate disappearance at 1710 cm⁻¹. Batch records from a 1000 L glass-lined reactor (Pfaudler AE-series) operated under cGMP per ICH Q7 §12.1 indicate that charging the phosphite reagent at a rate of 0.8–1.2 kg/min while maintaining the internal temperature at 22±2°C suppresses the formation of the dimeric ether impurity, which otherwise co-elutes with the desired product on a Waters XBridge C18 column (150×4.6 mm, 5 µm) under acetonitrile/20 mM phosphate buffer (pH 6.8) at 1.0 mL/min and absorbs at 265 nm. The dimer is assigned as m/z 229.1 [M+H]⁺ by single-quadrupole LC-MS in positive electrospray mode.

Additionally, the final API requires a nitrosamine risk assessment per EM(E)A/CHMP/428590/2021. Potential carryover of nitrite scavengers or dimethylamine from solvent recovery loops is evaluated by headspace GC-MS on a Thermo Scientific Trace 1610 with a TriPlus 500 headspace autosampler, achieving an LOQ of 0.03 ppm for N-nitrosodimethylamine. Suppliers of thiazole-5-methanol destined for GMP intermediates must provide a formal statement of compliance with REACH Annex XVII and a residual palladium certificate of analysis using USP <233> method (limit ≤10 µg/g). This level is validated via inductively coupled plasma-optical emission spectrometry (ICP-OES) on an Agilent 5900 with detection at 340.458 nm (Pd).

The 5-hydroxymethyl group of thiazole-5-methanol exhibits a distinctive propensity for selective esterification under Mitsunobu conditions (DIAD, PPh₃, THF, 0°C to rt) without competing ring-opening of the thiazole. This is exploited in the synthesis of strobilurin fungicide analogs, where the resulting esters modulate cuticular penetration in cereal rust control. Process development at the 100 g scale in a Radleys Reactor-Ready system with an overhead stirrer indicated a significant heat spike during DIAD addition (ΔT_adiabatic ≈ 35°C). Scale-up to a 50 L jacketed stainless steel reactor (Büchi ULTRA) necessitated a controlled addition protocol over 90 min with a jacket setpoint of −5°C and a cooling capacity of 850 W to maintain the reaction mass below 8°C. Off-spec material generated by a thermal excursion displayed an additional byproduct, identified as the thiazole ring-sulfoxide (m/z 131.1), originating from oxidation by the DEAD-related hydrazine byproduct; specification for this impurity is ≤0.15%.

What Explains the Divergent Reactivity of Thiazole-5-Methanol in Palladium-Catalysed Couplings Compared to the 2-Isomer?

The position of the hydroxymethyl substituent exerts a profound influence on the kinetics of cross-coupling. In Suzuki-Miyaura reactions with phenylboronic acid and Pd(PPh₃)₄ (2 mol%) in THF/water (3:1) using K₂CO₃ at 65°C, thiazole-5-methanol-derived bromide (5-bromomethylthiazole) achieves >95% conversion within 3 h, while the 2-isomer requires >12 h for a comparable outcome. In-situ FTIR monitoring (ReactIR 15 with a SiComp probe) reveals that the oxidative addition step is rate-determining for both substrates, but the activation energy for the 5-isomer is approximately 9 kcal/mol lower, attributable to reduced steric clash between the Pd(0) center and the thiazole ring in the transition state. The nitrogen atom at the 3-position of the thiazole ring remains unencumbered in the 5-isomer, allowing rapid ligand substitution; by contrast, the 2-isomer’s proximity of the bulky hydroxymethyl group to the metal centre retards coordination. This effect is exacerbated in Buchwald-Hartwig aminations employing Xantphos and Pd₂(dba)₃, where the 5-isomer gives 85% isolated yield of the N-aryl derivative under 1 atm N₂ at 100°C after 8 h, while the 2-isomer yields only 22% under identical conditions due to competing proto-dehalogenation.

Consequently, for library synthesis in fragment-based drug discovery, thiazole-5-methanol is preferred whenever C-2 or C-4 functionalization is required without blocking group installation. However, the presence of the free hydroxyl imposes a limitation in Negishi couplings involving organozinc reagents: the OH group must be protected as a THP-ether or TBS-ether prior to transmetallation to avoid quenching the reactive zinc species. In a typical procedure, TBS-Cl (1.2 eq.) and imidazole (2.5 eq.) in DMF are used, and the completion of silylation is verified by the disappearance of the broad O–H stretch at 3400 cm⁻¹ in the IR spectrum; the resulting silyl ether remains stable through the coupling but must be cleaved with TBAF (1.0 M in THF) in a subsequent step, generating fluoride-containing waste that demands compliance with local disposal regulations (EU Directive 2008/98/EC).

When Handling Scalable Grignard Chemistry with the 5-Hydroxymethyl Group

Direct application of Grignard reagents to unprotected thiazole-5-methanol is impossible due to the acidity of the alcoholic proton (pK_a ≈ 13.5). The hydroxyl is therefore converted to a stable siloxane or alkoxyalkyl ether before metalation. For large-scale work, the pyranyl protection using 3,4-dihydro-2H-pyran (DHP) with catalytic pyridinium p-toluenesulfonate (0.05 eq.) in dichloromethane at 20°C is favoured because it proceeds without DMF-related regulatory concerns. The protected intermediate is then subjected to a Grignard exchange or addition. In a representative sequence executed in a 2000 L Hastelloy C-22 reactor (De Dietrich), the solution of the protected thiazole in THF (water content <50 ppm by Coulometric Karl Fischer) was cooled to −15°C using a Lauda Integral XT process chiller before the controlled addition of iPrMgCl·LiCl (1.3 M in THF, 1.1 eq.) over 2 h. The dosing rate was regulated by a Bronkhorst mini CORI-FLOW mass flow controller, and the jacket was interlocked with a safety PLC (Siemens SIMATIC S7-1500F) programmed to a SIL 2 trip at internal temperature −5°C to prevent runaway acceleration. The exotherm displayed a maximum heat release rate of 65 W/kg during the initial 20% of the addition; above this point, the system approached a semi-batch steady state. After quench with aq. NH₄Cl, the product was extracted and the THP group cleaved under mild acidic hydrolysis (Amberlyst 15 H⁺ resin, MeOH/water) to regenerate the free alcohol without thiazole ring degradation.

Typical commercial release specifications for thiazole-5-methanol
Property	Specification	Acceptance Criterion	Method
Appearance	White to off-white crystalline powder	Conforms	Visual inspection (Ph.Eur. 2.2.1)
Assay (anhydrous, solvent-free)	≥98.0%	98.5–101.5%	GC, FID, DB-5 column (30 m × 0.25 mm, 0.25 µm)
Melting range	Lit. 42–46°C	41–48°C	Differential Scanning Calorimetry, 10°C/min, N₂
Water (Karl Fischer)	≤0.5%	0.15–0.45%	coulometric, oven method 150°C
Residual solvents (GC-HS)	THF ≤0.072%, MTBE ≤0.5%	Per ICH Q3C options 2	USP <467> Class 2
Lead (Pb)	≤2 µg/g	0.1–1.2 µg/g	ICP-MS (USP <233>)
Related substances (total)	≤2.0%	0.8–1.8%	HPLC-UV, 210 nm

Kinetic differences between thiazole-5-methanol and its isomers extend beyond metal-catalyzed reactions. In acid-catalysed esterification with acrylic acid, the 5-isomer reaches equilibrium within 4 h at 80°C using 1.2 eq. of acid and 0.5 wt% p-toluenesulfonic acid, whereas the 4-isomer requires 12 h to achieve a similar conversion. This behaviour is exploited in continuous flow setups where residence time distribution is critical. Employing a Vapourtec R-Series flow reactor with a 10 mL PFA coil at 100°C and 12 bar back pressure, the 5-isomer throughput reached 15 g/h with no detectable oligomer formation, whereas the 4-isomer plugged the reactor due to precipitated dimer after 45 min of operation. Published data for the direct comparison of isomer stabilities in long-term photostressed solutions remains limited; however, accelerated testing (45°C, 75% RH, ICH Q1A) on thiazole-5-methanol in amber glass vials shows 0.2% degradation over 3 months, primarily to the corresponding aldehyde (thiazole-5-carboxaldehyde), while the 2-isomer under identical conditions generates 1.8% of aldehyde plus an unidentified polar peak.

Preventing Oxidative Dimerisation During Long-Term Storage

Bulk quantities of thiazole-5-methanol are prone to gradual discolouration and the formation of an ether-linked dimer (bis(5-thiazolylmethyl) ether) when exposed to atmospheric oxygen, even at sub-ambient temperatures. The dimerisation follows radical-mediated auto-oxidation and is catalysed by trace metals such as Fe²⁺ and Cu⁺. To suppress this, incoming shipments from the manufacturer are packaged in 25 kg capacity UN 4G-certified HDPE drums lined with a double PE antistatic bag, with a nitrogen blanket applied until the oxygen headspace concentration falls below 0.5% (measured by a Mocon PAC CHECK 450 EC). An OxySorb oxygen absorber sachet and a reversed-phase silica gel desiccant are placed inside the inner bag to maintain an environment of <5% RH. For aliquots stored in R&D laboratories, transfer into 100 mL amber borosilicate bottles under an argon atmosphere in a glovebox (H₂O <1 ppm, O₂ <1 ppm) and subsequent storage at −20 ± 5°C extends the retest period to 24 months with no detectable dimer by HPLC. Containers that have been opened repeatedly must be re-qualified after 30 days using the Karl Fischer and GC assay methods listed in the specification table. No antioxidant is added to avoid interference with downstream catalytic steps.

Isomeric thiazole-methanol comparison — key physicochemical and application attributes
Isomer	CAS No.	Melting point (°C)	Primary synthetic utility	Typical purity (GC)
Thiazole-2-methanol	13750-68-1	34–38 (lit.)	2-Aminothiazole building block; chelating ligand precursor	≥97.0%
Thiazole-4-methanol	6727-43-6	48–52 (lit.)	Heterocyclic core for Factor Xa inhibitor intermediates	≥97.5%
Thiazole-5-methanol	38527-46-5	42–46 (lit.)	Cephalosporin C-3 side-chain synthesis; strobilurin ester handle	≥98.0%

The fate of thiazole-5-methanol in continuous flow reductive amination was investigated on an Asia Syrris system using a packed-bed reactor containing Raney nickel at 60°C and 5 bar H₂. The primary amine product, essential for a series of factor XIa inhibitors, was generated with 91% conversion at a residence time of 8 min. In contrast, thiazole-2-methanol under the same conditions yielded a complex mixture containing 12% of ring-hydrogenated byproducts due to competitive adsorption on the catalyst, confirming the superior selectivity imparted by the remote substitution pattern. Such data underpin the selection of the 5-isomer for multi-kilogram campaigns where hydrogenation selectivity determines the economic viability of the route. Equipment cleaning validation swab limits for thiazole-5-methanol as a non-cytotoxic intermediate are set at 0.25 µg/cm² based on a health-based exposure limit of 50 µg/day, consistent with the EMA guideline on shared facilities.